Biology subjects

Moyes, D. L.

Publications and source records attributed to Moyes, D. L..

10 recordsLinked to original sources

bioRxiv2026

Isoleucine and asparagine influence the growth of staphylococcal strains in atopic dermatitis

Atopic dermatitis (AD) is a multifactorial, chronic skin disease associated with microbial factors. It is known that staphylococcal skin microbes play a role in the pathophysiology of AD, notably S. aureus. However, how staphylococcal strain variation affects disease aetiology and progression remains unclear. Using a culture-dependent approach, we analyzed the genomic and phenotypic profile of staphylococcal strains isolated from a Hong Kong children cohort (n = 70). Presence of S. aureus was positively associated with AD skin, whilst S. epidermidis and S. hominis were positively associated with healthy skin, but no overall strain type was associated with AD. In vitro experimentation revealed that there is demarcation in S. aureus strain growth, biofilm biomass formation, and metabolite production by disease severity. While isoleucine and asparagine promoted S. aureus growth, these amino acids suppressed S. hominis growth. These collective findings highlight the importance of strain-level and metabolic interactions of staphylococci in AD pathophysiology.

microbiology↗

bioRxiv2025

Metabolic imprinting drives epithelial memory during mucosal fungal infection

Epithelial cells at barrier sites are emerging as active participants in innate immune memory, yet the underlying metabolic and epigenetic mechanisms remain unclear. Here, we uncover a previously unrecognized form of trained immunity in oral epithelial cells that enhances protection against fungal infection. Using a mouse model, we show that mucosal exposure to Candida albicans confers sustained protective memory that is independent of adaptive immunity and myeloid cells. Mechanistically, mucosal memory is driven by proline catabolism via proline dehydrogenase (Prodh) in epithelial cells, which sustains mitochondrial function, epigenetic remodeling, and promotes cytokine production upon secondary challenge. Unlike classical trained immunity in immune cells, epithelial memory is independent of glycolysis but partially sustained by fatty acid oxidation via carnitine palmitoyltransferase-I (CPT1). These findings uncover a distinct metabolic-epigenetic axis that underlines long-term epithelial memory in the oral mucosa and reveal novel non-hematopoietic mechanisms of mucosal defense against fungal pathogens.

immunology↗

bioRxiv2025

Enhanced Computational and Experimental Approaches for Comparative Analysis of the Human Mycobiome

The mycobiome is now recognized as a critical part of the human microbial ecosystem, playing a significant role in both health and disease. Mycobiome research is currently in its infancy and relies on fungal-specific primers with challenges in bioinformatics to accurately determine the structure of the mycobiota community. In addition, the majority of computational and experimental methods currently in use have been optimized for bacteria rather than for fungi. Here, we provide a comparative analysis of extraction methodologies for metagenome sequencing and subsequent bioinformatic analysis that will enhance fungal species identification. We utilized cultured mock fungal communities, including both yeast and mold species, to evaluate the efficiency of extraction protocols. We further enhanced computational analysis of the mycobiome, using mock and human metagenome data together with our curated catalogue consisting of 984 fungal genomes specific to the human mycobiome. Application of this optimised workflow for oral and gut samples of healthy individuals detected of novel species from Puccinia and Lentinus genera among the established presence of Malassezia, Rhizophagus, Candida and Saccharomyces genera. In addition, Enterocytozoon, was identified specifically in the gut mycobiome. Our pipeline enabled the comprehensive sampling of all fungal genes in a microbial community within a human sample minimising bias, reducing errors and artefacts from amplification, and providing accurate diversity and abundance data for the human mycobiome.

genomics↗

bioRxiv2025

Candida albicans enhances melanoma cell aggressiveness through p38-MAPK and HIF-1α pathways and metabolic reprogramming

Recent studies have increasingly focused on the role of fungi, including Candida albicans, in carcinogenesis. Since C. albicans is a component of the human microbiota, particularly on the skin, we investigated its effect on the phenotype and signalling pathways of melanoma cells. Assays for migration, adhesion, angiogenesis, and hepatic metastasis showed that C. albicans promotes a more malignant phenotype in melanoma cells. At the transcriptomic level, C. albicans increased the expression of VEGF (Vegfa), and genes associated with MAPK and HIF-1 signalling pathways, and with aerobic glycolysis. Further in vitro analysis revealed that TLRs and EphA2 receptors are involved in the recognition of live C. albicans, stimulating VEGF secretion and expression of the AP-1 transcription factor component c-Fos through p38-MAPK and HIF-1. These pathways also regulate the expression of other AP-1 constituents such as Atf3, Jun, and Jund. Moreover, p38-MAPK regulates glycolytic genes like Hk2, Slc2a1, and Eno2. In conclusion, C. albicans activates the p38-MAPK/c-Fos/AP-1 and HIF-1/HIF-1/c-Fos/AP-1 pathways in melanoma cells, promoting a pro-angiogenic environment and metabolic reprogramming. Therefore, this study clarifies the impact of C. albicans on melanoma cells, which can lead to the use of antifungal therapies as complementary to traditional treatments for melanoma.

microbiology↗

bioRxiv2023

EGR1 regulates oral epithelial cell responses to Candida albicans via the EGFR- ERK1/2 pathway

Candida albicans is a fungal pathobiont colonising mucosal surfaces of the human body, including the oral cavity. Under certain predisposing conditions, C. albicans invades mucosal tissues activating EGFR-MAPK signalling pathways in epithelial cells via the action of its peptide toxin candidalysin. However, our knowledge of the epithelial mechanisms involved during C. albicans colonisation is rudimentary. Here, we describe the role of the transcription factor early growth response protein 1 (EGR1) in human oral epithelial cells (OECs) in response to C. albicans. EGR1 expression increases in OECs when exposed to C. albicans independently of fungal viability, morphology, or candidalysin release, suggesting EGR1 is involved in the fundamental recognition of C. albicans, rather than in response to invasion or pathogenesis. Upregulation of EGR1 is mediated by EGFR via Raf1, ERK1/2 and NF-{kappa}B signalling but not PI3K/mTOR signalling. Notably, EGR1 mRNA silencing impacts on anti-C. albicans immunity, reducing GM-CSF, IL-1 and IL-1{beta} release, and increasing IL-6 and IL-8 production. These findings identify an important role for EGR1 in priming epithelial cells to respond to subsequent invasive infection by C. albicans and elucidate the regulation circuit of this transcription factor after contact.

immunology↗

bioRxiv2022

PaliDIS: A tool for fast discovery of novel insertion sequences

The diversity of microbial insertion sequences, crucial mobile genetic elements in generating diversity in microbial genomes, needs to be better represented in current microbial databases. Identification of these sequences in microbiome communities presents some significant problems that have led to their underrepresentation. Here, we present a bioinformatics pipeline called Palidis that recognises insertion sequences in metagenomic sequence data rapidly by identifying inverted terminal repeat regions from mixed microbial community genomes. Applying Palidis to 264 human metagenomes identifies 879 unique insertion sequences, with 519 being novel and not previously characterised. Querying this catalogue against a large database of isolate genomes reveals evidence of horizontal gene transfer events across bacterial classes. We will continue to apply this tool more widely, building the Insertion Sequence Catalogue, a valuable resource for researchers wishing to query their microbial genomes for insertion sequences. Data SummaryO_LIPalidis is available here: github.com/blue-moon22/palidis C_LIO_LIThe Insertion Sequence Catalogue is available to download here: https://github.com/blue-moon22/ISC C_LIO_LIThe raw reads from the Human Microbiome Project can be retrieved using the download links provided in Supplementary Data 1 C_LIO_LIThe analysis for this paper is available here: github.com/blue-moon22/palidis_paper_analysis C_LIO_LIThe output of Palidis that was run on these reads is available in Supplementary Data 2 C_LI Impact StatementInsertion sequences are a class of transposable element that play an important role in the dissemination of antimicrobial resistance genes. However, it is challenging to completely characterise the transmission dynamics of insertion sequences and their precise contribution to the spread of antimicrobial resistance. The main reasons for this are that it is impossible to identify all insertion sequences based on limited reference databases and that de novo computational methods are ill-equipped to make fast or accurate predictions based on incomplete genomic assemblies. Palidis generates a larger, more comprehensive catalogue of insertion sequences based on a fast algorithm harnessing genomic diversity in mixed microbial communities. This catalogue will enable genomic epidemiologists and researchers to annotate genomes for insertion sequences more extensively and advance knowledge of how insertion sequences contribute to bacterial evolution in general and antimicrobial resistance spread across microbial lineages in particular. This will be useful for genomic surveillance, and for development of microbiome engineering strategies targeting inactivation or removal of important transposable elements carrying antimicrobial resistance genes.

genomics↗

bioRxiv2022

EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin

Candida albicans (C. albicans) is a dimorphic human fungal pathogen that can cause severe oropharyngeal candidiasis (OPC, oral thrush) in susceptible hosts. During invasive infection, C. albicans hyphae invade oral epithelial cells (OECs) and secrete candidalysin, a pore-forming cytolytic peptide that is required for fungal pathogenesis at mucosal surfaces. Candidalysin induces cell damage and activates multiple MAPK-based innate signaling events that collectively drive the production of downstream inflammatory mediators. The activities of candidalysin are also dependent on the epidermal growth factor receptor (EGFR), but how these signals are integrated is undefined. Here, we identified five essential adaptor proteins as key mediators of the epithelial response to C. albicans infection on cultured OECs, including growth factor receptor bound protein 2 (Grb2), Grb2-associated-binding protein 1 (Gab1), Src homology and collagen (Shc), SH2 containing protein tyrosine phosphatase-2 (Shp2) and casitas B-lineage lymphoma (c-Cbl). All these signaling effectors were inducibly phosphorylated in response to C. albicans, in a candidalysin-dependent mechanism but additionally required EGFR phosphorylation, matrix metalloproteinases (MMPs) and cellular calcium flux. Of these, Gab1, Grb2 and Shp2 were the dominant drivers of ERK1/2 signaling and production of downstream cytokines. Together, these results identify the key adaptor proteins that drive EGFR signaling mechanisms, which determine oral epithelial responses to C. albicans.

microbiology↗

bioRxiv2021

Aspergillus fumigatus drives tissue damage via iterative assaults upon mucosal integrity and immune homeostasis

The human lung is constantly exposed to Aspergillus fumigatus spores, the most prevalent worldwide cause of fungal respiratory disease. Pulmonary tissue damage is a unifying feature of Aspergillus-related diseases; however, the mechanistic basis of damage is not understood. In the lungs of susceptible hosts A. fumigatus undergoes an obligatory morphological switch involving spore germination and hyphal growth. We modelled A. fumigatus infection in cultured A549 human pneumocytes, capturing phosphoactivation status of five host signalling pathways, nuclear translocation & DNA binding of eight host transcription factors, and expression of nine host response proteins over six time points encompassing exposures to live fungus and the secretome thereof. The resulting dataset, comprised of more than 1000 data points, reveals that pneumocytes mount differential responses to A. fumigatus spores, hyphae and soluble secreted products via the NF-kB, JNK, and JNK + p38 pathways respectively. Importantly, via selective degradation of host pro-inflammatory (IL-6 and IL-8) cytokines and growth factors (FGF-2), fungal secreted products reorchestrate the host response to fungal challenge as well as driving multiparametric epithelial damage, culminating in cytolysis. Dysregulation of NF-kB signalling, involving iterative stimulation of canonical and non-canonical signalling, was identified as a significant feature of host damage both in vitro and in a mouse model of invasive aspergillosis. Our data demonstrate that composite tissue damage results from iterative exposures to different fungal morphotypes and secreted products and suggest that modulation of host responses to fungal challenge might represent a unified strategy for therapeutic control of pathologically distinct types of Aspergillus-related disease. IMPORTANCEPulmonary aspergillosis is a spectrum of diseases caused primarily by Aspergillus fumigatus. This fungus is ubiquitous in the environment and grows as a mold, which harbors and disperses spores into the environment. Like other airborne pathogens, the lung mucosa is the first point of contact with the fungus post inhalation. The outcome and severity of disease depends on the host-fungal interaction at the lung interface. We studied how the human lung interacts with spore, germ tube and hyphae growth forms to understand the sequence and dynamics of the early events, which are critical drivers of disease development and progression. Our work is significant in identifying, in response to fungal secreted products, non-canonical NF-kB activation via RelB as being a driving factor in fungus-mediated lung damage. This process could be modulated therapeutically to protect the integrity of infected lung mucosae.

microbiology↗

bioRxiv2020

The human oral phageome is highly diverse and rich in jumbo phages

Until recently, the contribution of bacteriophages to the composition and function of the human microbiome has been largely overlooked. Recent developments in discovering novel bacteriophages from human metagenomes have been mostly focused on the gut. Here we profile and compare the phageome of 633 human oral sites and 221 paired gut phageomes acquired from countries worldwide. Phageome profiles are specific to oral sites and the gut across individuals, with the largest separation between the oral cavity and the gut. The differences in phage genotypes is bolstered by distinct phage host compositions between these sites. The greatest diversity of phages is found on the tongue and in dental plaque. Notably, 37 unique circular jumbo phage genomes were identified in oral sites, particularly on the dorsum of the tongue, whilst none were found in the gut. Oral sites provide conducive environments, such as robust biofilms, that can harbour genetically diverse phages.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗

bioRxiv2019

Abundance and diversity of resistomes differ between healthy human oral cavities and gut

The global threat of the \"antimicrobial resistance apocalypse\" that has arisen in recent years has driven the use of high-throughput sequencing techniques to monitor the profile of resistance genes, known as the \"resistome\", in microbial populations. The human oral cavity contains a poorly explored reservoir of these genes, and little is known about their abundance and diversity, or how their profile compares with antimicrobial resistance genes in the gut. Here we analyse the resistome profiles of 788 oral cavities worldwide and compare these profiles with paired stool samples from shotgun metagenomic data. We find country and body site-specific differences in the prevalence of antimicrobial resistance genes, classes and mechanisms in oral and stool samples. However, the abundance of these antimicrobial resistance classes do not correlate with antibiotic prescription rates. A greater similarity was found in interpersonal resistomes between the same body sites than intrapersonal resistomes across different body sites. Between individuals, the oral cavity contains the highest and lowest abundances of specific antimicrobial resistance genes, but a lower diversity of resistance genes compared to the gut, which is likely influenced by differences in microbial composition and exposure to antimicrobial selection pressures. Co-occurrence analysis shows contrasting ARG-species associations between saliva and stool samples. This is the first study to date that characterises the oral cavity resistome worldwide, identifying its distinctive signatures compared to the gut.Maintenance and persistence of antimicrobial resistance is likely to vary across different body sites. Thus, we highlight the importance of characterising the resistome across body sites to uncover the antimicrobial resistance potential in the human body.

microbiology↗